Introduction
Coronavirus Disease 2019 (COVID-19) is the latest global health threat
and, as in two preceding instances of the emergence of coronavirus
respiratory disease, poses critical challenges for the public health,
research, and medical communities (1, 2). Although the pathology of
COVID-19 is now well described, the mechanisms underlying disease
progression remain unclear. While a robust vaccination campaign and the
further development of vaccines against SARS-CoV-2, the causal agent of
COVID-19, are underway, a variety of investigational therapeutic
approaches are also being explored (3). Dexamethasone, plitidepsin, and
monoclonal antibody therapies, such as toclilizumab and eculizumab, have
shown promise in lowering soluble inflammatory markers part of the
cytokine storm and reducing severe outcomes in COVID-19 (4-7). Further
elucidating effector molecules responsible for disease progression to
determine effective interventions earlier in the course of the disease
is needed in order to help design effective therapies to ameliorate
disease manifestations and its complications (8-10).
The scope and severity of COVID-19 varies among those infected. Some
patients exhibit no or minor flu-like symptoms and quick recovery, some
have sustained fever and have persistent fatigue with a post-viral
syndrome, while others experience serious lung involvement that requires
hospitalization that may lead to death (11). Although the respiratory
and the gastrointestinal system are initial targets for SARS-CoV-2,
there clearly is a systemic nature to this disease in severe cases that
may be driven by micro-emboli and inflammatory processes (12, 13). While
follow up in natural history studies will likely uncover additional
post-infection sequelae, the notable impairment in type-I interferon
responses and rapid lymphopenia clearly plays a role in disease severity
(14-16), highlighting the need for novel therapeutics that take into
consideration the mechanism(s) of infection, viral replication, and
effector pathways that lead to COVID-19 associated pathologies.
Inflammasome activation in peripheral immune cells and tissues was
recently observed in COVID-19 patients and the level of
inflammasome-derived products, including active caspase-1, associated
with disease severity and poor outcomes (17). We recently reported that
caspase-1 expression in lymphocytes and serum IL-18 levels are increased
in liver transplant patients acutely ill with SARS-CoV-2 infection
suggesting pyroptosis mechanisms may play role in severe COVID-19 (18).
A recent study showed that SARS-CoV-2 infection of rhesus macaques led
to an upregulation of caspase-1 molecular signature in peripheral blood
cells as early as day 2 post-inoculation (19). Pyroptosis, also known as
caspase-1-dependent cell death, is inherently inflammatory, triggered by
various pathological stimuli (i.e. stroke, heart attack, cancer),
crucial for controlling microbial infections (20-22), and characterized
by rapid plasma-membrane rupture and the release of pro-inflammatory
intracellular contents (23, 24), a marked contrast to the regulated
death process of apoptosis (25). Insight into the complex activation and
regulation of the inflammasome complex and the way in which COVID-19
intersects with this pathway is an area of significant investigation
(26). Thus, strategies targeting the inflammasome/pyroptosis pathway
upstream of the production of the effector cytokines may be a novel
approach to reverse COVID-19 induced immune perturbations (27). Building
on our previous findings, we sought to expand our analysis to
investigate caspase-1 activity in SARS-CoV-2 infection, as well as the
role of other caspases, including in red blood cells (RBCs) given the
significance of COVID-19 associated coagulopathies (28, 29).